Pyrimethamine-based pharmaceutical compositions and methods for fabricating thereof

ABSTRACT

Pharmaceutical compositions that include aqueous suspensions of therapeutically effective quantity of a diaminopyrimidine compound (such as pyrimethamine) are provided herein. Methods for fabricating and using the compositions, and kits that include the compositions are also described.

CROSS REFERENCE TO RELATED APPLICATION(S)

This is a continuation-in-part application and claims the benefit ofpriority under 35 U.S.C. § 120 to U.S. Ser. No. 16/433,679, filed Jun.6, 2019, now pending, which claims the benefit of priority under 35U.S.C. § 119(e) of U.S. Ser. No. 62/682,632, filed Jun. 8, 2018, theentire content of each of which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates generally to the field of pharmaceuticalsand more specifically to pharmaceutical compositions that include as anactive component therapeutically effective quantity of adiaminopyrimidine compound (such as pyrimethamine), and to methods ofpreparing and using such compositions.

BACKGROUND

Pyrimethamine has been used for a long time to treat a variety ofdiseases and conditions such as, e.g., malaria. According to sometheories, the health benefits attributable to pyrimethamine stem from itbeing a powerful inhibitor of the dihydrofolate reductase of plasmodiaand other species, thereby blocking the biosynthesis of purines andpyrimidines, which are essential for DNA synthesis and cellmultiplication.

In spite of a significant body of evidence in favor of usingpyrimethamine, it has been determined that it may not work as well insome cases. One serious drawback is the fact that there are instanceswhere individuals, infants, children and adults who cannot swallowtablets, require a liquid form of the medication; however,pyrimethamine's solubility in water is poor.

It is, therefore, desirable to have pyrimethamine-based pharmaceuticalcompositions that are free from drawbacks and deficiencies, e.g., tohave such compositions in a stable, liquid dosage form. This patentspecification discloses such pharmaceutical compositions that canachieve such positive patient outcomes, and methods of fabricating andadministering the same.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a pictorial diagram showing an exemplary pharmaceutical kitaccording to various embodiments of the present invention.

SUMMARY

According to various embodiments of the invention, a pharmaceuticalcomposition formulated as a suspension is provided, the compositioncomprising a dispersed phase of particles comprised of a therapeuticallyeffective quantity of at least one diaminopyrimidine compound, orderivatives or analogs thereof, and an anhydrous dispersion medium, andfurther including at least one pharmaceutically acceptable surfactant orsolubilizing and suspending agent, and optionally, at least onederivative of folic acid, wherein the dispersed phase is dispersedwithin the dispersion medium.

According to various embodiments of the invention, the diaminopyrimidinecompound may be any of pyrimethamine, trimetrexate, iclaprim,trimethoprim, 2,4-diaminopyrimidine, 4,5-diaminopyrimidine, orpiritrexim, or any combination thereof.

According to various embodiments of the invention, the derivative offolic acid that may be used is leucovorin.

According to various embodiments of the invention, the anhydrousdispersion medium comprises at least one of a vegetable oil (e.g.,castor oil, soybean oil, coconut oil, avocado oil, olive oil, almondoil) and a medium chain triglyceride.

According to various embodiments of the invention, the pharmaceuticallyacceptable surfactant or solubilizing and suspending agent may be any ofnon-ionic polyoxyethlene-polyoxypropylene block copolymers, awater-soluble derivative of cellulose, optionally partially cross-linkedpolyacrylates, polyoxyethylene sorbitan monolaurates, polyoxyethylenesorbitan monopalmitates, polyoxyethylene sorbitan monostearates,polyoxyethylene sorbitan monooleates, glyceryl distearate, triglycerolmonooleate, and combinations thereof.

According to various embodiments of the invention, the pharmaceuticalcompositions described herein may be orally administered to a mammaliansubject in need of treatment for any of various diseases and/or maladies(e.g., toxoplasmosis, isosporiasis, cystoisosporiasis, actinomycosis,pneumocystis jirovecii pneumonia, various myelodysplastic syndromes suchas leukemia, and amyotrophic lateral sclerosis).

According to yet additional embodiments, the invention providespharmaceutical kits. The kits may contain a storage container containingthe pharmaceutical suspension as described herein, a cup having outsidemarkings corresponding to the quantity of the diaminopyrimidinecompound, or derivatives or analogs thereof in the suspension, at leastone packet containing a quantity of the derivative of folic acid,wherein the quantity of the derivative of folic acid corresponds to thequantity of the diaminopyrimidine compound, or derivatives or analogsthereof, and a stirrer. In various embodiments, the kit may include abox for storing these elements, and may further include instructions foruse enclosed within the box or affixed thereto.

DETAILED DESCRIPTION A. Terms and Definitions

Unless specific definitions are provided, the nomenclatures utilized inconnection with, and the laboratory procedures and techniques ofanalytical chemistry, synthetic organic and inorganic chemistrydescribed herein, are those known in the art. Standard chemical symbolsare used interchangeably with the full names represented by suchsymbols. Thus, for example, the terms “hydrogen” and “H” are understoodto have identical meaning. Standard techniques may be used for chemicalsyntheses, chemical analyses, formulating compositions and testing them.The foregoing techniques and procedures can be generally performedaccording to conventional methods well known in the art.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention claimed. As used herein, theuse of the singular includes the plural unless specifically statedotherwise. The section headings used herein are for organizationalpurposes only and are not to be construed as limiting the subject matterdescribed.

As used herein, “or” means “and/or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as“includes,” and “included,” is not limiting.

“About” as used herein means that a number referred to as “about”comprises the recited number plus or minus 1-10% of that recited number.For example, “about” 100 degrees can mean 95-105 degrees or as few as99-101 degrees depending on the context. Whenever it appears herein, anumerical range such as “1 to 20” refers to each integer in the givenrange; i.e., meaning only 1, only 2, only 3, etc., up to and includingonly 20, as well as to the numbers in between integers, e.g., 1.5 or2.5, and the like.

The term “pharmaceutical composition” is defined as a chemical or abiological compound or substance, or a mixture or combination of two ormore such compounds or substances, intended for use in the medicaldiagnosis, cure, treatment, or prevention of disease or pathology.

The term “suspension” is defined for the purposes of the presentapplication as a two-phase solid-in-liquid dispersion system having afirst phase and a second phase. In other words, “suspension” is definedas a heterogeneous mixture in which the solute particles (i.e., thoseforming the solid phase) do not truly dissolve, but get suspendedthroughout the bulk of the solvent instead, without undergoing anysignificant precipitation within prolonged periods of time. It isfurther specifically provided that dispersion systems having three, fouror more phases are not within the meaning of “suspension” for thepurposes of the instant application.

Therefore, the above mentioned first phase of the suspension consists ofa multitude of solid particles and is designated and defined as thedispersed phase, and the above mentioned second phase of the suspensionis also a liquid and is designated and defined as the dispersion medium,or, interchangeably and synonymously, the continuous phase.

Furthermore, the dispersed phase is dispersed in the dispersion medium,and the term “dispersed” is defined as meaning that the dispersed phaseis statistically evenly distributed within the continuous phasethroughout the entire volume of the suspension, with no statisticallymeaningful deviations in the concentrations of the dispersed phase indifferent portions of the suspension.

The term “stability” for the purposes of the present application refersto the ability of the dispersion to retain the pre-determined quantityof an active component (e.g., pyrimethamine) after the pre-determinedperiod of storage time has expired. The storage may be at roomtemperature or at an elevated temperature, e.g., about 40° C.

A dispersion of this invention is defined as being stable if it stillcontains not less than about 90% and not more than about 110% of theoriginal quantity of the active component (e.g., pyrimethamine) aftereach of the following periods of storage time: 30, 60, 90, and 150 days.If the quantity of the active component (e.g., pyrimethamine) is morethan about 110% as measured by the UHPLC assay it is indicative ofexcessive undesirable flocculation of the particles of the dispersion.Such products are considered unacceptable. If the quantity is less thanabout 90% as measured by the same method it is indicative of excessiveundesirable degradation of the active component (due to chemicaldestruction or any other cause), and such products are likewiseconsidered unacceptable.

The term “medium-chain triglycerides” refers to triglycerides (i.e.,tri-esters of glycerol and fatty acids) in which at least two of thethree fatty acids moieties are derived from aliphatic (i.e., saturatedopen-chain) acids having between 6 and 12 carbon atoms; the fatty acidsthat are used for making medium-chain triglycerides are defined asmedium-chain fatty acids and are caproic (IUPAC, hexanoic), enanthic(IUPAC, heptanoic), caprylic (IUPAC, octanoic), pelargonic (IUPAC,nonanoic), capric (IUPAC, decanoic), undecylic acid (IUPAC, undecanoic),or lauric (IUPAC, dodecanoic) acids.

The term “carrier” refers to a substance that serves as a vehicle forimproving the efficiency of delivery and the effectiveness of apharmaceutical composition.

The term “solubilizing agent” for the purposes of the instantapplication refers broadly to chemical compounds that improve theprocess of incorporating the solubilizate (i.e., active componentsdescribed herein) into micelles; in other words the presence of asolubilizing agent makes the process of solubilization faster, easier,and/or more complete compared with compositions without it.

The term “suspending agent” used herein interchangeably with the term“emulsifier” for the purposes of the instant application refers broadlyto chemical compounds that help active pharmaceutical ingredients staysuspended in the formulation and prevents and/or reduces the phaseseparation of two-phase dispersion systems described herein.

The term “therapeutically effective amount” is defined as the amount ofthe compound or pharmaceutical composition that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought by the researcher, medical doctor or other clinician.

The term “pharmaceutically acceptable” when used to define a carrier,whether diluent or excipient, refers to a substance that is compatiblewith the other ingredients of the formulation and not deleterious to therecipient thereof.

The terms “administration of a composition” or “administering acomposition” are defined to include an act of providing a compound ofthe invention or pharmaceutical composition to the subject in need oftreatment.

B. Embodiments of the Invention

According to embodiments of the present invention, pharmaceuticalcompositions intended to prevent and/or treat various diseases andmaladies, such as toxoplasmosis, malaria, isosporiasis,cystoisosporiasis, actinomycosis, pneumocystis jirovecii pneumonia,leukemia, or amyotrophic lateral sclerosis, are provided. Thepharmaceutical compositions of the instant invention are free ofsulfonamide.

In various embodiments, the compositions of the invention may beprovided in the form of a suspension. The suspensions include, consistof, or consist essentially of, an anhydrous dispersion medium (i.e., thecontinuous phase), a dispersed phase that is dispersed within thedispersion medium, and a pharmaceutically acceptable carrier. Thedispersed phase includes, consists of, or consists essentially of,particles of a therapeutically effective quantity of at least onediaminopyrimidine compound (an active component), or derivatives oranalogs thereof, and optionally may further include at least onederivative of folic acid, if desired. The dispersion medium includes atleast one of a vegetable oil or a medium chain triglyceride, and furthercomprises at least one emulsifier or solubilizing and suspending agent.

Specific examples of the acceptable diaminopyrimidine compounds that maybe used according to the embodiments of the invention include, withoutlimitation, pyrimethamine (also known under the trade name DARAPRIM®,Glaxosmithkline LLC, Wilmington, DE), trimetrexate, iclaprim,trimethoprim, 2,4-diaminopyrimidine, 4,5-diaminopyrimidine, andpiritrexim. These compounds are also listed in Table 1, below, includingtheir respective chemical IUPAC names and structures:

TABLE 1 Diaminopyrimidine Compounds Compound IUPAC Name ChemicalStructure Pyrimethamine 5-(4-chlorophenyl)-6-ethyl-pyrimidine-2,4-diamine

Trimetrexate 5-methyl-6-[(3,4,5- trimethoxyphenyl)aminomethyl]quinazoline-2,4-diamine

Iclaprim 5-[(2-cyclopropyl-7,8-dimethoxy- 2H-chromen-5-yl)methyl]pyrimidine-2,4-diamine

Trimethoprim 5-(3,4,5- trimethoxybenzyl)pyrimidine-2,4- diamine

2,4-diaminopyrimidine Pyrimidine-2,4-diamine

4,5-diaminopyrimidine Pyrimidine-4,5-diamine

Piritrexim 6-[(2,5-dimethoxyphenyl)methyl]-5-methylpyrido[2,3-d]pyrimidine- 2,4-diamine

Those having ordinary skill in the art may use (an)otherdiaminopyrimidine(s) instead of, or in combination with, the above-nameddiaminopyrimidine-based compound(s), if desired.

The mass concentration of pyrimethamine and/or (an)otherdiaminopyrimidine-based compound(s) in the composition may be betweenabout 0.1% and about 5.0%, such as between about 0.5% and about 2.0%,for example, about 0.5%, 1.0%, 1.5% or 2%, preferably about 1.0%.

If derivative(s) of folic acid is(are) present in the compositions ofthe instant invention, one specific example of such acceptablederivative is, without limitation, folinic acid (leucovorin, that is,2-{[4-[(2-amino-5-formyl-4-oxo-5,6,7,8-tetrahydro-1H-pteridin-6-yl)methylamino]benzoyl]amino}pentanedioic acid, according to the IUPAC), which is anorganic compound having the following chemical structure:

Those having ordinary skill in the art may use (an)other derivative(s)of folic acid instead of, or in combination with, folinic acid, ifdesired. If derivative(s) of folic acid is(are) present in thecompositions of the instant invention its(their) mass concentration inthe composition may be between about 0.1% and about 5.0%, such asbetween about 0.5% and about 2.0%, for example, about 0.5%, 1.0%, 1.5%or 2%, preferably about 1.0%.

As mentioned above, the anhydrous dispersion medium of the compositionof the present invention includes at least vegetable oil or at least onemedium chain triglyceride or a combination of products of both classes.The dispersion medium forms the major portion of the composition, itsmass concentration in the composition being between about 80.0% andabout 99.0%, such as between about 85.0% and about 95.0%, for example,about 85.0%, 85.5%, 90.0%, 90.5%, 91.0%, 91.5%, 92.0%, 92.5%, 93.0%,93.5%, 94.0%, 94.5%, or 95.0%, preferably about 95.0%.

Specific examples of the acceptable vegetable oils that may be used inthe anhydrous dispersion medium according to various embodiments of theinvention include, without limitation, castor oil, soybean oil, coconutoil, avocado oil, olive oil, almond oil, and combinations thereof.Partially hydrogenated oils can be also used, for example, polyoxyl 40hydrogenated castor oil. Those having ordinary skill in the art may use(an)other vegetable oil(s) instead of, or in combination with, thosementioned above, if desired. Those having ordinary skill in the art willunderstand that all these oils represent complex blend of organiccompounds, as opposed to individual organic molecules.

For example, castor oil is a complex mixture of several fatty acids,principally, ricinoleic acid, an unsaturated, 18-carbon fatty acidhaving a hydroxyl functional group on the 12^(th) carbon (IUPAC,12-hydroxyoctadec-9-enoic acid). Those having ordinary skill in the artwill understand that castor oil has a very complex chemical structureand is a mixture of triglycerides that varies, but commonly comprisesricinoleic acid (about 80%) plus triglycerides of linoleic (IUPAC,9,12-octadecadienoic) and oleic (IUPAC, octadec-9-enoic) acids (about20% combined).

Almond oil is another complex mixture of several fatty acids, whichvaries but typically comprises 65 to 70 mass % of oleic, 20 to 25% oflinoleic, up to 4% of palmitic (IUPAC, hexadecanoic) and smallquantities of palmitoleic (IUPAC, hexadec-9-enoic) and stearic (IUPAC,octadecanoic) acids.

Coconut oil is yet another complex mixture of several fatty acids, whichalso varies, but commonly comprises about 45 to 50% of lauric acid, thebalance being a combination of other medium-chain fatty acids describedabove, as well as palmitic and stearic acids.

Olive oil is yet another mixture of several fatty acids, which alsovaries, but its principal ingredient is oleic acid (about 75 to 85%),the balance being a combination of other fatty acids including linoleicand palmitic acids.

A variety of medium-chain triglyceride can be used for forming theanhydrous dispersion medium. For example, triglyceride(s) containing thealiphatic tails derived from caprylic acid or caproic acid may be soused. Those having ordinary skill in the art may use (an)othermedium-chain triglyceride(s) instead of, or in combination with, thosebased on caprylic or caproic acids, if desired. One specific productcomprising medium-chain triglycerides that may be used is UNISPEND®anhydrous sweetened liquid (Fagron, Inc., St. Paul, Minn.).

As stated above, the anhydrous dispersion medium used herein furthercomprises at least one emulsifier or solubilizing and suspending agentwhich may be present in the compositions of the instant invention atmass concentrations between about 0.1 mass % and about 10.0 mass% , suchas between about 1.0 mass % and about 5.0 mass %, for example, about 1.0mass %, 1.5 mass %, 2.0 mass %, 2.5 mass %, 3.0 mass %, 3.5 mass %, 4.0mass %, 4.5 mass % or 5.0 mass %, preferably about 3.0 mass %.

Those having ordinary skill in the art will choose the most appropriateemulsifier or solubilizing and suspending agent. For example, one suchemulsifier or solubilizing and suspending agent that may be used is anon-ionic polyoxyethlene-polyoxypropylene block copolymer having thefollowing general structure:

HO—CH₂—CH₂O) _(x)—(C₃H₆—O)_(y)—(CH₂—CH₂—O)_(x)—H,

wherein in the chemical structure above x is an integer having the valueof at least 8 and y is an integer having the value of at least 38.Polyoxyethlene-polyoxypropylene block copolymer(s) that can be used maybe those belonging to the Pluronic® or Poloxamer® families, chemically,poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethyleneglycol), both available from BASF Corp. and from several other vendorsand having the following general chemical structure:

One more specific and non-limiting example of a non-ionicpolyoxyethlene-polyoxypropylene block copolymer that can be used is theproduct known under the trade name PLURONIC® L64, which is described bythe chemical structure above, with the molecular weight of thepolyoxypropylene portion of about 1,750 Daltons, about a 40%polyoxyethylene content (mass), and the average overall molecular weightof about 2,900 Daltons. Another specific non-limiting example of anon-ionic polyoxyethlene-polyoxypropylene block copolymer that can beused is the product known under the trade name Poloxamer 407 ® (alsoknown as PLURONIC® F127), which is also described by the chemicalstructure above, with the molecular weight of the polyoxypropyleneportion of about 4,000 Daltons, about a 70% polyoxyethylene content(mass), the overall molecular weight of between about 9,840 Daltons andabout 14,600 Daltons.

Some non-limiting examples of other emulsifiers or solubilizing andsuspending agents that may be used in combination with, or instead of,non-ionic polyoxyethlene-polyoxypropylene block copolymers, includederivatives of cellulose, optionally partially cross-linkedpolyacrylates, polyoxyethylene sorbitan monolaurates, polyoxyethylenesorbitan monopalmitates, polyoxyethylene sorbitan monostearates,polyoxyethylene sorbitan monooleates (e.g., members of POLYSORBATE®family of products), glyceryl distearate, triglycerol monooleate, andpolysaccharide thickening agents such as xanthan gum.

For example, suitable derivatives of cellulose that may be used include,without limitations, carboxymethyl cellulose, methyl cellulose,hydroxyethyl cellulose, and hydroxypropyl cellulose (Dow Chemical,Midland, Mich.). Examples of acceptable partially cross-linked,polyacrylates that may be used include, without limitations, such aspolymers of the CARBOPOL® family (Lubrizol, Wickliffe, Ohio). Typically,the cross-linking agents that may be used to cross-link suchpolyacrylates are allyl sucrose or allyl pentaerythritol.

Suitable products of POLYSORBATE® family (i.e., ethoxylated sorbitanesterified with fatty acids) that may be used include, withoutlimitations, polyoxyethylene sorbitan monolaurates, polyoxyethylenesorbitan monopalmitates, polyoxyethylene sorbitan monostearates, orpolyoxyethylene sorbitan monooleates, some of which are also known asTWEEN® products, such as POLYSORBATE® 80) (Croda, Wilmington, Del.).

One typical product of the latter family that can be used is Polysorbate80 ® (chemically, polyoxyethylene (20) sorbitan monooleate, also knownas sorbitan mono-9-octadecenoate poly(oxy-1,2-ethanediyl), i.e., aproduct of polycondensation of polyethoxylated sorbitan and oleic acidhaving 20 units derived from ethylene glycol), which is a nonionicsurfactant and emulsifier.

Those having ordinary skill in the art will realize that yet (an)otheradditional emulsifier(s) or solubilizing and suspending agent(s) may beused if desired and will select such supplemental emulsifier(s) orsolubilizing and suspending agent(s), as well as to choose the quantitythereof.

According to various embodiments of the present application, thepharmaceutical compositions described herein are formulated as stabletwo-phase suspensions as defined above. More specifically, according tothese embodiments, the suspensions consist of two phases, i.e., thedispersed phase that is dispersed within the dispersion medium. Thedispersed phase includes particles comprising a therapeuticallyeffective quantity of the pharmaceutically active component, i.e., adiaminopyrimidine compound, or derivatives or analogs thereof. In someembodiments, no compounds other than the diaminopyrimidine compoundsdescribed hereinabove are present within the particles that form thedispersed phase. According to such embodiments, the dispersion medium isa liquid that includes all other compounds that are present in thepharmaceutical compositions described in the application. Theapplication envisions no embodiment where diaminopyrimidine compound canbe used outside the dispersed phase such as being a part of thedispersion medium.

In various embodiments, in addition to diaminopyrimidine compounds orderivatives or analogs thereof, the dispersed phase may optionallycontain other compounds, such as, without limitation, stabilizers,antioxidants, preservatives, caking agents (e.g., colloidal silicadioxide), various flavoring agents or sweeteners.

According to various embodiments, methods for fabricating theabove-described pharmaceutical compositions are provided. A one-batchformulation method may be used, where the components of thepharmaceutical formulation can be combined in a single container; thecomponents may be added to the container simultaneously orconsecutively. Those having ordinary skill in the art can choose thebest method for preparing the compositions.

Pharmaceutical compositions prepared as described above can be used totreat, prevent or alleviate toxoplasmosis, malaria, isosporiasis,cystoisosporiasis, actinomycosis, pneumocystis jirovecii pneumonia,myelodysplastic syndromes (e.g., leukemia), and amyotrophic lateralsclerosis.

In further embodiments, pharmaceutical compositions prepared asdescribed above can be used to enhance efficacy of one or more immunecheckpoint inhibitors to improve effectiveness of such products whenthey are used for treating, e.g., cancer, as well as for any otherpurpose. In such treatments, pyrimethamine may be administered prior to,concurrent with, and subsequent to a checkpoint inhibitor.

More specifically, checkpoint inhibitors the efficacy of which may be soimproved include, without limitations, those inhibitors that compriseone or more endpoints selected from tumor regression, tumorstabilization, reduction in tumor growth, inhibition of metastasis,stabilization of metastasis, reduction of metastatic growth,encapsulation of tumor and/or metastasis, augmentation of cytokinesassociated with tumor inhibition, decrease in cytokines associated withtumor progression, suppression of angiogenesis, augmentation of tumorinfiltrating lymphocytes, switch of intratumoral macrophages from M2 toM1 phenotype, augmentation of tumor infiltrating dendritic cells,reduction of tumor associated T regulatory cells, and reduction in tumorassociated myeloid suppressor cells.

Checkpoint inhibitors may include agents capable of suppressingexpression or activity of such molecules as PD-1, PD-L1, CTLA-4, PD-L2,LAG3, Tim3, 2B4, A2aR, ID02, B7-H3, B7-H4, BTLA, CD2, CD20, CD27, CD28,CD30, CD33, CD40, CD52, CD70, CD112, CD137, CD160, CD226, CD276, DR3,OX-40, GAL9, GITR, ICOS, HVEM, IDO1, KIR, LAIR, LIGHT, MARCO, PS, SLAM,TIGIT, VISTA, STAT3, or VTCN1. Exemplary checkpoint inhibitors include,but are not limited to, nivolumab, pembrolizumab, ipilimumab,tremelimumab, BMS-936559, durvalumab, atezolizumab, avelumab, MPDL3280A,MEDI4736, MSB0010718C, and MDX1105-01.

Pharmaceutical formulations described herein can be typically deliveredorally. An ordinarily skilled physician may prescribe delivery by anyother acceptable method if so desired and indicated; for instance, thosehaving ordinary skill in the art may, if appropriate and medicallyindicated, alternatively choose such methods of delivery as intravenous,intramuscular, intratumoral injection, or parenterally or nasally.

It will be understood by those having ordinary skill in the art that thespecific dose level and frequency of dosage for any particular patientmay be varied and will depend upon a variety of factors including theactivity of the specific compound employed, the metabolic stability andlength of action of that compound, the age, body weight, general health,gender, diet of the subject being treated, and the severity of theparticular disease or condition being treated. In one purely exemplaryembodiment the dosage may be 25 mg to 100 mg once daily.

In additional embodiments, pharmaceutical kits are provided. The kitincludes a sealed container approved for the storage of pharmaceuticalcompositions, the container containing one of the above-describedpharmaceutical compositions. An instruction for the use of thecomposition and information about the composition are to be included inthe kit and/or affixed to the box housing the kit.

More specifically, one exemplary but non-limiting embodiment of a kitthat is considered within the scope of the present invention isillustrated schematically in FIG. 1. As shown in FIG. 1, the kit 100includes a storage container 1 in which a suspension 12 comprising anactive component is stored. In various embodiments, the suspensioncomprises:

(a1) a dispersed phase consisting of particles comprising atherapeutically effective quantity of at least one diaminopyrimidinecompound, or derivatives or analogs thereof;

(a2) at least one and pharmaceutically acceptable surfactant orsolubilizing and suspending agent; and

(a3) an anhydrous dispersion medium,

wherein the dispersed phase is dispersed within the dispersion medium.

In various embodiments, the kit 100 further includes a disposable orreusable cup 2 having disposed thereon a plurality of markings 3, whereeach of the plurality of markings corresponds to a predeterminedquantity of the diaminopyrimidine compound (element a1of the suspension12), or derivatives or analogs thereof in the selected amount of theabove described suspension 12. For example, the following illustrationsapply to compositions in which the diaminopyrimidine compound ispyrimethamine.

In the pyrimethamine-based embodiments, the plurality of markings 3(which may be optionally color-coded) may indicate, for example, thequantities of about 25 mg, about 50 mg, or about 75 mg of pyrimethaminethat would be contained in the quantity of the pyrimethamine-basedsuspension 12, if the suspension 12 is poured from the container 1 intothe cup 2 up to the level indicated by each of the markings 3. Thus, invarious embodiments, the cup 2 may have disposed thereon, three markings3 indicating, e.g., 25 mg, 50 mg, and 75 mg. In various embodiments, themarkings 3 may be applied to the cup 2 to indicate different quantitiesof the active component. Those having ordinary skill in the art maychoose their own quantities as desired.

In various embodiments, the kit 100 further includes at least one packet4 containing a quantity of the derivative of folic acid 7, wherein thequantity of the derivative of folic acid 7 corresponds to the quantityof the diaminopyrimidine compound, or derivatives or analogs thereof.The specific derivative of folic acid 7 may be pre-selected and can be,e.g., folinic acid (leucovorin) and the quantity of the derivative maybe preliminarily calculated by those having ordinary skill in the art.Thus, FIG. 1 illustrates an exemplary embodiment where three packets 4of folinic acid 7 are provided in the kit 100. The first packet 4 a ofthe three packets 4 may contain about 2.5 mg of folinic acid 7, whichwould correspond to the lowest level of pyrimethamine to beadministered, e.g., 25 mg of pyrimethamine, 1:10 ratio. The secondpacket 4 b may contain about 5.0 mg of folinic acid 7, which wouldcorrespond to the medium level of pyrimethamine to be administered,e.g., 50 mg of pyrimethamine, same ratio. The third packet 4 c maycontain about 7.5 mg of folinic acid 7, which would correspond to thehighest level of pyrimethamine to be administered, e.g., 75 mg ofpyrimethamine, same ratio.

In various embodiments, the kit 100 may further include a reusable ordisposable stir rod or stirrer 5 (which may be made of wood, plastic,glass, metal or any other appropriate material), a box 10 for storingthe components of the kit 100, and instructions for use 15 enclosedwithin the box 10 or affixed thereto.

During use of the kit 100, a user may prepare a medicament by pouringthe suspension 12 from the container 1 into the cup 2, up to apre-selected marking 3 (e.g., low, medium or high). Then, using thestirrer 5, the contents of a corresponding packet 4 can be mixed in, atwhich point the medicament is ready to be administered.

The following examples are provided to further elucidate the advantagesand features of the present invention but are not intended to limit thescope of the invention. The examples are for the illustrative purposesonly. USP pharmaceutical grade products were used in preparing theformulations described below.

C. EXAMPLES Example 1. Preparing a Pharmaceutical Composition #1

A pharmaceutical composition #1 was prepared as described below. Thefollowing products were used in the amounts specified:

(a) about 1.0 g of solid powdered pyrimethamine;

(b) about 0.1 g of solid powdered leucovorin calcium (1.08 g ofleucovorin calcium is equivalent to 1.0 g of leucovorin);

(c) about 0.11 g of solid powdered xanthan gum;

(d) about 0.2 mL of POLYSORBATE® 80;

(e) about 100 mL of Unispend® anhydrous sweetened medium chaintrigylceride;

(f) about 1.5 mL of artificial caramel flavor liquid; and

(g) a small quantity of glycerol sufficient to wet the powders asmentioned below.

Pyrimethamine, leucovorin calcium, and xantham gum were combined usingmortar and pestle according to standard technique of mixing solids, thenthe mixture was triturated to achieve uniformity. A small quantity ofglycerol was added just to wet the powder followed by trituration againto form a smooth paste.

The artificial caramel flavor liquid and POLYSORBATE® 80 were thenadded, with trituration followed by adding the anhydrous sweetenedmedium chain trigylceride, and the product was transferred to thedispensing bottle. Finally, the mortar was washed using a small quantityof anhydrous sweetened medium chain trigylceride, and the wash wastransferred to the bottle, to ensure the entire quantity of activecomponents has been so transferred followed by packaging and labeling.

Example 2. Preparing a Pharmaceutical Composition #2

A pharmaceutical composition #2 was prepared as described below. Thefollowing products were used in the amounts specified:

(a) about 4.0 g of solid powdered pyrimethamine;

(b) about 0.4 g of butylated hydroxytoluene;

(c) about 0.9 g of powdered sodium benzoate;

(d) about 0.4 g of solid powdered xanthan gum;

(e) about 4.0 g of POLYSORBATE® 80;

(f) about 6.0 mL of artificial caramel flavor liquid; and

(g) about 400 mL of caprylic/capric tryglycerides liquid.

Pyrimethamine, butylated hydroxytoluene, sodium benzoate, and xanthamgum were combined using mortar and pestle according to standardtechnique of mixing solids, then the mixture was triturated to achieveuniformity. A small quantity of glycerol was added just to wet thepowder followed by trituration again to form a smooth paste.

The artificial caramel flavor liquid and Polysorbate® 80 were thenadded, with trituration followed by adding the caprylic/caprictryglycerides, and the product was transferred to the dispensing bottle.Finally, the mortar was washed using a small quantity of caprylic/caprictryglycerides, and the wash was transferred to the bottle, to ensure theentire quantity of active components has been so transferred followed bypackaging and labeling.

Example 3. Preparing a Pharmaceutical Composition #3

A pharmaceutical composition #3 was prepared. The same components in thesame quantities were used as described in Example 2, above, except thatcaprylic/capric tryglycerides liquid used in the composition of Example2 was replaced by sweet almond oil in the same quantity of about 400 mL.The process of mixing the components for composition #3 was also thesame as that described in Example 2.

Compositions #2 and #3 prepared as described above were then tested forstability chromotographically by UHPLC assaying. The results are shownin Table 1 below.

TABLE 2 Stability of Compositions of Examples 2 and 3 Quantity ofPyrimethamine Assayed, % of the Original Quantity, After a period ofStorage Time at room temperature at 40° C. Day Day Day Day Day Day DayDay Day Day Composition 0 30 60 90 150 0 30 60 90 150 From 106 106 102108 108 105 104 101 108 n/a Example 2 From 98 98 97 102 98 98 98 98 102n/a Example 3

As can be seen from the results summarized in Table 1, both dispersionsdescribed in Example 2 (containing caprylic/capric tryglycerides liquid)and in Example 3 (containing sweet almond oil) possess sufficientstability at each point in time during being stored up to 150 days, atroom temperature (˜25° C.) and up to 90 days at 40° C.

Example 4. Preparing a Pharmaceutical Composition #4

A pharmaceutical composition #4 was prepared as described below. Thefollowing products were used in the amounts specified:

(a) about 4.0 g of solid powdered pyrimethamine;

(b) about 0.4 g of butylated hydroxytoluene;

(c) about 8.0 g of colloidal micronized silicone dioxide;

(d) about 0.4 g of solid powdered xanthan gum;

(e) about 1.6 g of polyoxyl 40 hydrogenated castor oil;

(f) about 4.0 g of POLYSORBATE® 80;

(g) about 0.8 g of acesulfame potassium;

(h) about 6.0 mL of artificial caramel flavor liquid; and

(i) about 400 mL of caprylic/capric tryglycerides liquid.

Components (a)-(i) were mixed to yield composition #4. The process ofmixing the components for composition #4 was also the same as thatdescribed in Example 2 (and SiO₂ was mixed together with other solids).

Although the invention has been described with reference to the aboveexamples, it will be understood that modifications and variations areencompassed within the spirit and scope of the invention. Accordingly,the invention is limited only by the following claims.

What is claimed is:
 1. A method for preparing a medicament for treatinga disease selected from the group consisting of toxoplasmosis, malaria,isosporiasis, cystoisosporiasis, actinomycosis, pneumocystis jiroveciipneumonia, myelodysplastic syndromes, and amyotrophic lateralsclerosiscomprising, the method comprising: (a) preparing a suspensioncomprising: (a1) a dispersed phase consisting of particles comprising atherapeutically effective quantity of at least one diaminopyrimidinecompound, or derivatives or analogs thereof; (a2) at least onepharmaceutically acceptable surfactant or solubilizing and suspendingagent; and (a3) an anhydrous dispersion medium, wherein the dispersedphase is dispersed within the dispersion medium; (b) placing thesuspension into a cup having disposed thereon a plurality of markings,each marking corresponding to a predetermined quantity of element (a1);and (c) using a stirrer to mix a quantity of at least one derivative offolic acid into the suspension, wherein the quantity of the derivativeof folic acid corresponds to the quantity of element (a1), therebypreparing the medicament.
 2. The method of claim 1, wherein thediaminopyrimidine compound is selected from the group consisting ofpyrimethamine, trimetrexate, iclaprim, trimethoprim,2,4-diaminopyrimidine, 4,5-diaminopyrimidine, piritrexim, and anycombination thereof.
 3. The method of claim 2, wherein thediaminopyrimidine compound is pyrimethamine.
 4. The method of claim 1,wherein the derivative of folic acid is leucovorin.
 5. The method ofclaim 1, wherein the anhydrous dispersion medium comprises at least onevegetable oil or at least one medium chain triglyceride, or anycombination thereof.
 6. The method of claim 5, wherein the vegetable oilis selected from the group consisting of castor oil, soybean oil,coconut oil, avocado oil, olive oil, almond oil, and combinationsthereof.
 7. The method of claim 5, wherein the medium chain triglycerideis a triglyceride having at least two of the three fatty acids moietiesthat are derived from saturated open-chain acids having between 6 and 12carbon atoms.
 8. The method of claim 7, wherein the saturated open-chainacids are selected from the group consisting of caprylic acid andcaproic acid.
 9. The method of claim 1, wherein the acceptablesurfactant or solubilizing and suspending agent is selected from thegroup consisting of non-ionic polyoxyethlene-polyoxypropylene blockcopolymers, a water-soluble derivative of cellulose, optionallypartially cross-linked polyacrylates, polyoxyethylene sorbitanmonolaurates, glyceryl distearate, triglycerol monooleate,polyoxyethylene sorbitan monopalmitates, polyoxyethylene sorbitanmonostearates, and polyoxyethylene sorbitan monooleates.
 10. The methodof claim 9, wherein the non-ionic polyoxyethlene-polyoxypropylene blockcopolymer is poly(ethylene glycol)-block-poly(propyleneglycol)-block-poly(ethylene glycol).
 11. The method of claim 9, whereinthe water-soluble derivative of cellulose is selected from the groupconsisting of carboxymethyl cellulose, methyl cellulose, hydroxyethylcellulose, and hydroxypropyl cellulose.
 12. The method of claim 9,wherein the solubilizing and suspending agent is polyoxyethylene (20)sorbitan monooleate.
 13. The method of claim 3, wherein the massconcentration of pyrimethamine in the composition is between about 0.1%and about 5.0%.
 14. The method of claim 1, wherein the compositionretains between about 90% and about 110% of the diaminopyrimidinecompound after being stored at room temperature for each of 30, 60, 90and 150 days and up to about 40° C. for each of 30, 60, and 90 days. 15.The method of claim 1, wherein the quantity of element (a1) is 25 mg, 50mg, or 75 mg.
 16. A pharmaceutical kit, comprising: (a) a containercontaining a suspension, wherein the suspension comprises: (a1) adispersed phase consisting of particles comprising a therapeuticallyeffective quantity of at least one diaminopyrimidine compound, orderivatives or analogs thereof; (a2) at least one pharmaceuticallyacceptable surfactant or solubilizing and suspending agent; and (a3) ananhydrous dispersion medium, wherein the dispersed phase is dispersedwithin the dispersion medium; (b) a cup having disposed thereon aplurality of markings, each marking corresponding to a predeterminedquantity of element (al1; (c) at least one packet containing a quantityof a derivative of folic acid, wherein the quantity of the derivative offolic acid corresponds to the quantity of element (a1); (d) a stirrer;(e) a box configured to store elements (a)-(d); and (f) instructions foruse enclosed within the box or affixed thereto.
 17. The kit of claim 16,wherein the cup has three markings, wherein each marking indicates thequantities of 25 mg, 50 mg, and 75 mg, respectively, of element (a1).18. The kit of claim 16, wherein the diaminopyrimidine compound isselected from the group consisting of pyrimethamine, trimetrexate,iclaprim, trimethoprim, 2,4-diaminopyrimidine, 4,5-diaminopyrimidine,piritrexim, and any combination thereof.
 19. The kit of claim 18,wherein the diaminopyrimidine compound is pyrimethamine.
 20. The kit ofclaim 16, wherein the derivative of folic acid is leucovorin.